The Impact of Bioceramic Scaffolds on Bone Regeneration in Preclinical In Vivo Studies: A Systematic Review
Abstract
:1. Introduction
2. Materials and Methods
2.1. Focal Question
2.2. Eligibility Criteria
2.2.1. Inclusion Criteria
- Publication written in English.
- Randomized or non-randomized controlled animal experimental studies with at least two study groups and at least 6 animals per group.
- Use of experimental critical-sized bone defect (CSD) in non-medically compromised animals.
2.2.2. Exclusion Criteria
- In vitro studies, clinical studies, reviews, meta-analyses, conference proceedings, book chapters.
- Animal studies reporting ectopic models (e.g., subcutaneous).
- Absence of an empty defect and/or autogenous bone and/or deproteinized bovine-derived bone substitutes control group.
- Treatment of periodontal defects.
- Studies using scaffolds loaded with chemotherapeutic agents, anti-inflammatory drugs, antibiotics.
2.3. Search Strategy, Screening Method, and Data Extraction
2.4. Outcome Measures
2.4.1. Primary Outcomes
2.4.2. Secondary Outcomes
2.5. Quality Assessment and Risk of Bias Analysis
2.6. Data Synthesis and Statistical Analysis
3. Results
3.1. Study Selection
3.2. Study Characteristics
3.2.1. Studies in Rabbits—Main Features
3.2.2. Studies in Rats—Main Features
3.3. Study Quality and Risk of Bias Assessment
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Animal | Defect Site | Dimension of CSD | References |
---|---|---|---|
Mouse | Calvaria | 4 mm diameter | [33] |
Segmental long-bone defect | Radius: 4 mm Femur: 5 mm | [34] | |
Rat | Calvaria | Unilateral/central:8 mm diameter; bilateral: 5 mm diameter | [23] |
Cylindric defect | Femur: 2 mm in diameter and 3 mm in length | [35] | |
Segmental long-bone defect | Radius: 1 cm diameter | [36] | |
Mandible | 4 mm diameter | [37] | |
Rabbit | Calvaria | Four defects: 8 mm diameter; unilateral defect: 15 mm diameter; bilateral defect: 11 mm diameter | [38] |
Segmental long-bone defect | Radius: defect > 1.4 cm involving periosteum | [39] | |
Cylindric defect | Femur: 6 mm in diameter and 5 mm in length; tibiae: 6 mm diameter | [40] (femur) [41] (tibiae) | |
Mandible | 5 mm diameter | [42] | |
Pig | Segmental long-bone defect | Femur: 7.6 cm; tibiae: 2 cm; radius: 2.5–3 cm; ulna: 2 cm | [34,36] |
Sheep | Calvaria | 22 mm in diameter | [43,44] |
Segmental long-bone defect | Femur: 2.5 cm; tibiae: 3–3.5 cm | [34] | |
Dog | Calvaria | 2 cm | [45] |
Segmental long-bone defect | Femur: 2.1–7 cm; radius: 0.3–2.5 cm; ulna: 2–2.5 cm | [34] | |
Segmental mandibular defect | 50 mm (in presence of periosteum); 15 mm (in absence of periosteum) | [46] |
Main Reason for Exclusion | No. | References |
---|---|---|
Language | 3 | [49,50,51] |
In vitro study | 2 | [52,53] |
Ectopic bone formation model | 4 | [54,55,56,57] |
Use of compromised animals | 4 | [58,59,60,61] |
Absence of a control group | 13 | [62,63,64,65,66,67,68,69,70,71,72,73,74] |
Control group other than empty defect and/or autogenous bone and/or deproteinized bovine-derived bone | 20 | [75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94] |
Unclear sample size | 5 | [95,96,97,98,99] |
Less than 6 animals per each test group | 4 | [100,101,102,103] |
Non-critical size bone defect | 11 | [104,105,106,107,108,109,110,111,112,113,114] |
Animal | Study Model | Number of Publications | References |
---|---|---|---|
Rabbit (n = 7) | Calvarial defect | 2 | [116,117] |
Dome model (calvaria) | 1 | [119] | |
Cylindrical femoral defect | 1 | [118] | |
Segmental radial defect | 1 | [120] | |
Mandibular square hole | 2 | [16,115] | |
Rat (n = 6) | Calvarial defect | 5 | [17,121,122,123,124] |
Cylindrical femoral defect | 1 | [125] |
Ref. | Biomaterial(s) | Production Method | Morphology | Porosity (%) | Density (g cm−3) | Elastic Modulus (MPa) | Compressive Strength (MPa) | In vitro Resorbability |
---|---|---|---|---|---|---|---|---|
[115] | PEEK-BBC composite doped with VEGF | HA + β-TCP bioceramic powder derived from extracted teeth, then impregnation in organic foam to prepare PEEK/BBC composite (calcined). Finally, immersion in polypeptide hydrogel containing VEGF. | Interconnected porous structure | 73.65 | - | - | - | - |
[16] | PEEK-BBC composite | HA + β-TCP bioceramic powder derived from extracted teeth, then impregnation in organic foam to prepare PEEK/BBC composite (calcined at 1250 °C). | Interconnected porous structure | - | - | - | - | - |
[116] | SLP CaSi | Direct ink writing | 3D porous structure | 58.3 ± 1.9 | - | ~55 (OSS) ~60 (TSS) | 25 (OSS) 25 (TSS) | - |
SLP CaSi–Mg6 | 53.1 ± 1.4 | - | ~135 (OSS) ~164 (TSS) | 81 (OSS) 103 (TSS) | - | |||
DLP CaSi | 59.2 ± 2.3 | - | ~45 (OSS) ~45 (TSS) | 18 (OSS) 18 (TSS) | - | |||
DLP CaSi–Mg6 | 53.5 ± 1.6 | - | ~90 (OSS) ~108 (TSS) | ~50 (OSS) ~63 (TSS) | - | |||
[117] | Multi-layered CaP/CaSi microspheres | Co-concentric capillary system | Microspheres | - | - | - | - | - |
[118] | (a) 50CS/PAA (b) 65CS/PAA (CS/PAA composites containing 50 and 65% (mass fraction) of CS) | in situ melting polymerization | Granules | - | - | - | - | WEIGHT LOSS: first 4 weeks: rapid degradation rate. Then, 50CS/PAA weight loss slow and subsequently steady. 65CS/PAA weight loss continued to increase. Total weight loss (after 16 weeks in SBF) 41.5% for 50CS/PAA and 56.2% for 65CS/PAA composite. SEM analysis: after 16 weeks of soaking, smoother surfaces. |
[119] | HA 60% + TCP 40% | Commercially available | Granules | - | - | - | - | - |
[120] | HA/TCP * | Emulsion process | 3D porous structure | - | - | - | - | - |
[17] | nHA/PLA | Porogen leaching technique (NaCl as porogen) | 3D porous structure | ~93 | - | - | - | WEIGHT LOSS: after 8 weeks in PBS: ~10% nHAP/PLA 50% PLGA |
[122] | PLA/HA | 3D printing (mini-deposition system) | 3D porous structure | 60.0 ± 1.5 | - | - | - | - |
β-TCP | Animal-derived | 3D porous structure | 60 ± 10 | - | - | - | - | |
[123] | HA | Chemical synthesis | Powder | - | - | - | - | - |
HaFS | HA + animal-derived FS | Mixture of HA powder and fibrin | - | - | - | - | - | |
[124] | β-TCP-AE | Base-catalysed sol–gel technique | 3D porous structure | - | 0.15 ± 0.01 (no heat treatment), 0.52 ± 0.02 (1000 °C) | - | - | - |
[121] | PLGA coated with Willemite (Zn2SiO4) | Electrospun PLGA nanofibers coated with willemite | Nanofibrous scaffold | - | - | - | - | - |
[125] | Merwinite Ca3Mg(SiO4)2 | Sol-gel | Granules | - | - | - | - | - |
HA | Commercially available | Powder | - | - | - | - | - |
Ref. | Sample Size (No. Animals) | Defect | Biomaterial(s) § | Control (Empty, DBBM, Autogenous Bone) § | Other Materials/ Treatments § | Stem Cells, Drugs, GFs | Sacrifice (Weeks) | Assessment Method(s) | Main Findings |
---|---|---|---|---|---|---|---|---|---|
[115] | 24 | Mandibular square hole 12 × 10 × 2 mm (length × width × depth) | PEEK-BBC composite doped with VEGF (n = 6) | Empty (n = 6) | (a) no surgery (n = 6) (b) sham group—surgery only, no defect (n = 6) | VEGF | 4, 8, 16 | Histological analysis; histomorphometric analysis; RT-PCR; Western blot; immunofluorescence | Histological and histomorphometric analyses: the dimension of the defects in the empty group could be significantly lessened in the test group (p < 0.05). RT-PCR: 8 and 16 weeks: test group had a much higher mRNA level of VEGF than the empty group. Western blot: VEGF lower in the empty group compared with the test group (p < 0.05). Immunofluorescence: protein level of VEGF in the test group was much higher than that in the empty group. |
[16] | 60 | Mandibular square hole 12 × 10 × 2 mm (length × width × depth) | PEEK-BBC composite (n = 15) | Empty (n = 15) | (a) no treatment (n = 15) (b) only molar groove exposition (n = 15) | - | 4, 8, 16 | Histological analysis; RT-qPCR; Western blot | Histological analysis: low osteocytes in the empty group at each timepoint; presence of osteocytes at 4 weeks and increased number at 8 and 16 weeks in the PEEK-BBC group. RT-qPCR: BMP-2 significantly higher in the PEEK group compared with the empty group at 8 and 16 weeks. Western blot: 8 weeks: expression of BMP-2 protein significantly upregulated by the PEEK-BBC composites treatment compared with the empty group. |
[116] | 24 | 8 mm ϕ calvarial bone defect (4 for each animal) | (a) SLP pure calcium silicate (CaSi); (b) SLP dilute Mg-doped CaSi (CaSi–Mg6); (c) DLP CaSi scaffold; (d) DLP CaSi–Mg6 | Empty (n = 4) | - | - | 4, 8, 12 | Histological analysis; histomorphometric analysis; micro-CT analysis | Histological and histomorphometric analyses: no inflammatory cells at 4 weeks in any group; at 12 weeks presence of mature bone with laminar structure both in CaSi and CaSi-Mg6 group; DLP CaSi group showed more new bone formation and a significant degradation of scaffold struts. Micro-CT: scaffold material decreased with time, while new bone formation increased overtime; the empty group revealed a very limited amount of bone regeneration; pure CaSi group showed limited material residual compared with the CaSi–Mg6 group, but more new bone tissue was intruded into the porous constructs of the pure CaSi scaffolds. |
[117] | 15 | 8 mm ϕ calvarial bone defect (4 for each animal) | (a) CaP microspheres; multi-layered microspheres with layer order: (b) CaP@CaSi@CaP; (c) CaSi@CaP@CaSi | Empty (n = 15) | - | - | 6, 12, 18 | Histological analysis; micro-CT analysis | Histological analysis: at 6 weeks no inflammation in all groups; at 18 weeks no difference between vessel concentration in all groups; at 6 weeks multinucleate cells were observed directly just onto the surface of the CaP@CaSi@CaP microspheres. Micro-CT: empty group not healed at 18 weeks; CaSi phase was preferentially biodegraded in both the external and internal layer; Tb.N increased with the BV/TV increasing; the new bone formation started from the periphery to the center of the defect. |
[118] | 48 | Unilateral (desumed) femoral bone defect (6.5 mm in ϕ, 6 mm in depth) | (a) 50CS/PAA (b) 65CS/PAA | Empty (n = 16) | - | - | 4, 12 | Histological analysis | Histological analysis: small amount of newly formed bone at both 4 and 12 weeks in the empty group; 50CS/ PAA granules exhibited a slower degradation than 65CS/PAA granules. |
[119] | 24 | Dome model (Ti barrier)—bilateral calvaria (8 mm ϕ Ti dome) | HA 60% + TCP 40% (4BoneTM) | (a) Empty (n = 12) (b) Autogenous blood (n = 12) c) DBBM (Bio-Oss®) (n = 12) | - | - | 4, 13 | Histological analysis; histomorphometric analysis; micro-CT analysis | Histological analysis: gap between the bone and the barrier in all groups; dense fibrous connective tissue between the titanium barrier and the bone in all groups; no sign of active bone formation in the first month, but active bone formation at 3 months; in the empty and autogenous blood groups loose connective tissue at 1 month, that mineralized at 3 months; in Bio-Oss® and test groups no material resorption was found at 1 month, while osteoclastic activity was found at 3 months. Micro-CT and histomorphometric analyses: after 1 month no statistically significant difference in bone volume augmentation among the groups; at the third month the increase in the amount of newly formed bone was statistically significant just between empty and Bio-Oss® groups. |
[120] | 36 | Unilateral segmental radial 15-mm bone defect | (a) HA/TCP * + autogenous rBMSC (n = 6) (b) HA/TCP * + allogenic rBMSC (n = 6) (c) HA/TCP * + ovine BMSCs (n = 6) (d) HA/TCP * + canine BMSCs (n = 6) (e) cell free HA/TCP * scaffold (n = 6) | Empty (n = 6) | - | autologous, allogenic, ovine, canine BMSCs | 13 | Histological/histopathological analysis; radiographic evaluation (multiple time points); SEM examinations | Histopathological analysis: average bone formation (histological score): (a) > (b) > (d) > (c) > (e) > (empty), respectively: 3.0; 2.7; 2.2; 1.9; 0.75; 0.2. Radiography: at 90 days bone formation mean values: (a) > (b) > (d) > (c) > (e) > (empty), respectively 12; 11.22; 11.20; 10.18; 06.05; 0.94. SEM: higher bone formation ad maturation, and higher scaffold degradation in group (a), followed by group (b); presence of new woven bone in the scaffold’s pores in groups (c) and (d); poor bone formation and scaffold resorption in group (e); no bone formation at the entire length of the defect in the empty group, which was filled with fibrous tissue. |
Ref. | Sample Size (No. Animals) | Defect | Biomaterial(s) § | Control (Empty, DBBM, Autogenous Bone) § | Other Materials/Treatments § | Stem Cells, Drugs, GFs | Sacrifice (Weeks) | Assessment Method(s) | Main Findings |
---|---|---|---|---|---|---|---|---|---|
[17] | 24 | 5 mm ϕ bilateral calvarial bone defect | (a) nHA/PLA + hBMSCs (n = 12) (b) nHA/PLA (n = 6) | Empty (n = 12) | (a) PLGA + hBMSCs (n = 12) (b) PLGA (n = 6) | hBMSCs | 8, 16 | Histological analysis; histomorphometric analysis; immunohistochemistry; radiography; (weight loss profile of the scaffold after in vivo implantation intramuscularly) | Histological analysis: 8 weeks: minimal amount of bone-like tissue in defect with nHA/PLA + hBMSCs while no bone regeneration in the other groups; 16 weeks: newly formed bone in defects with PLGA + hBMSCs was larger than that in defects with nHA/PLA + hBMSCs, loose connective tissue in defects filled with scaffolds alone without cells or left unfilled; no obvious residual scaffold material in all defects both at 8 and 16 weeks. Histomorphometric analysis: new bone formation percentage in PLGA + hBMSCs and nHA/PLA + hBMSCs groups was higher than in the others (P < 0.05). Radiography: 8 weeks: no significant bone regeneration in any groups; 16 weeks: no sign of bone regeneration found in defects filled with scaffolds alone without cells. Immunohistochemical analysis: both at 8 and 16 weeks no positive staining of osteocalcin in empty defects and defects filled with scaffolds alone, while positive staining in defects filled with scaffolds seeded with cells. |
[122] | 32 | 5 mm ϕ unilateral calvarial bone defect | (a) PLA (85% wt) + HA (15% wt) (n = 8) (b) β-TCP (n = 8) | Empty (n = 8) | DBM (n = 8) | - | 4, 8 | Histological analysis; immunohistochemical analysis; micro-CT analysis; hematological analysis | Histological analysis: new bone around and in contact with the biomaterials; blank group filled with compressed fibrous-connective tissue. Immunohistochemistry: osteocalcin and type I collagen expression: PLA + HA> β-TCP > DBM; new bone %: β-TCP> PLA + HA > DBM> blank group Micro-CT analysis: new bone areas in empty control group were less than in the other implanted groups at both timepoints; the results of total degradation rates showed no significant difference between 3DP PLA/HA scaffolds and DBM scaffolds at eight weeks and β-TCP had the lowest degradation rates in all groups; Hematological analysis: leukocyte cell counts and red blood cell levels were similar in all implanted groups at the four time points (12 days, and 4, 6 and 8 weeks after the surgery). |
[123] | 40 | 5 mm ϕ monolateral calvarial bone defect | (a) HA particles 8 mg (n = 10) (b) HA 8 mg + FS 8 mL (n = 10) | Empty (n = 10) | FS 8 mL (n = 10) | - | 2, 6 | Histological analysis; histomorphometric analysis; radiography | Histological and histomorphometric analyses: 2 weeks: new bone formation from the periphery to the center of the defect; higher bone formation in the HA + FS group. 6 weeks: presence of mature newly formed bone in treated group; higher bone formation and lower connective tissue amount in the HA + FS group than in the HA group. |
[124] | 19 | 8 mm ϕ unique calvarial bone defect | β-TCP-AE (n = 6) | Empty (n = 7) | AE (n = 6) | - | 4, 13 | Histological analysis; immunohistochemistry | Histological and immunohistochemical analyses: 4 weeks: both test groups showed intense inflammation-associated fibrosis; control group showed fibrous-inflammatory tissue with moderate degree of calcification; in β-TCP-AE group granulation tissue and presence of polymorphonuclear leukocytes, macrophages and fibroblasts. 13 weeks: β-TCP-AE almost totally degraded, and significantly less inflammatory cells than at 4 weeks, with presence of solid and compact bone islands; the empty control group exhibited a minimal ossification along the internal rim of the bone defect; only the β-TCP-AE group exhibited intense ossification. |
[121] | 30 | 8 mm ϕ unique calvarial bone defect (not central) | PLGA coated with Willemite (n = 10) | Empty (n = 10) | PLGA (n = 10) | - | 8 | Histological analysis; histomorphometric analysis; radiography; MSCT | Histological and histomorphometric analyses: highest bone reconstruction in animals treated with willemite-PLGA; enhanced collagen deposition willemite-PLGA group than in PLGA group. MSCT and radiography: no evidence of neo-tissue regeneration in the untreated animals; rats receiving willemite-PLGA had the highest bone regeneration; neo-tissue formation started from the periphery of the defect site toward the center. |
[125] | 24 | bilateral femoral bone defects (3 mm in ϕ, 2 mm in depth) | (a)granules of merwinite (n = 16) (b) HA (n = 16) | Empty (n = 16) | - | - | 2, 8 | Histological analysis | Histological analysis: 2 weeks: no bone formation in the HA group, but presence of loose and fibrous connective tissue; connective tissue and small bone islands in merwinite group; 8 weeks: new bone until the center of the merwinite scaffold; higher bone formation and scaffold degradation in the merwinite group than in HA one; presence of irregular trabecular bone and beginning of Harvesian system formation in some areas; the control untreated group presented connective tissue both at 2 and 8 weeks and a slower healing. |
References | 1. Ethical Statement | 2. Experimental Procedures | 3. Experimental Animals | 4. Randomization | 5. Allocation Concealment | 6. Sample Size Calculation | 7. Completeness of Information | 8. Blinding of the Evaluator | 9. Financial Conflict of Interest |
---|---|---|---|---|---|---|---|---|---|
[115] | 2 | 2 | 0 | 2 | 1 | 0 | 2 | 1 | 2 |
[16] | 2 | 2 | 2 | 0 | 1 | 0 | 2 | 1 | 2 |
[116] | 2 | 2 | 2 | 2 | 2 | 0 | 2 | 1 | 1 |
[117] | 2 | 2 | 2 | 2 | 1 | 0 | 2 | 1 | 2 |
[118] | 2 | 2 | 2 | 0 | 1 | 0 | 2 | 1 | 1 |
[119] | 2 | 2 | 2 | 1 | 1 | 0 | 2 | 1 | 2 |
[120] | 2 | 2 | 2 | 0 | 0 | 0 | 2 | 1 | 2 |
[17] | 2 | 2 | 2 | 2 | 1 | 0 | 2 | 1 | 1 |
[122] | 2 | 2 | 2 | 2 | 1 | 0 | 2 | 1 | 2 |
[123] | 2 | 2 | 2 | 1 | 1 | 0 | 2 | 1 | 1 |
[124] | 2 | 2 | 2 | 1 | 1 | 0 | 2 | 1 | 2 |
[121] | 2 | 2 | 2 | 2 | 1 | 0 | 2 | 1 | 1 |
[125] | 2 | 2 | 2 | 0 | 1 | 0 | 2 | 1 | 1 |
References | 1. Allocation Sequence Generation | 2. Baseline Characteristics | 3. Allocation Concealment | 4. Random Housing | 5. Blinding of Care Giver/Investigator | 6. Random Outcome Assessment | 7. Blinding of Outcome Assessor | 8. Incomplete Outcome Data Addressed | 9. Free from Selective Outcome Reporting | 10. Free from Other Sources of Bias |
---|---|---|---|---|---|---|---|---|---|---|
[115] | Yes | No | Unclear | Yes | Yes | Yes | No | Yes | Unclear | Yes |
[16] | Yes | Yes | Unclear | Yes | Yes | Yes | No | Yes | Unclear | Yes |
[116] | Yes | Yes | Yes | Yes | No | Yes | Unclear | Yes | Unclear | Yes |
[117] | Yes | Yes | Unclear | No | No | Yes | Unclear | Yes | Unclear | Yes |
[118] | Yes | Yes | Unclear | No | No | Yes | Unclear | Yes | Unclear | Yes |
[119] | Yes | Yes | Unclear | Yes | No | Yes | Unclear | Yes | Unclear | Yes |
[120] | Yes | Yes | Unclear | Yes | No | Yes | Yes | Yes | Unclear | Yes |
[17] | Yes | Yes | Unclear | No | No | Yes | No | Yes | Unclear | Yes |
[122] | Yes | Yes | Unclear | Yes | No | Yes | No | Yes | Unclear | Yes |
[123] | Yes | Yes | Unclear | No | No | Yes | No | Yes | Unclear | Yes |
[124] | Yes | Yes | Unclear | No | No | No | No | Yes | Unclear | Yes |
[121] | Yes | Yes | Unclear | No | No | No | No | Yes | Unclear | Yes |
[125] | Yes | Yes | Unclear | Yes | No | Yes | No | Yes | Unclear | Yes |
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Brunello, G.; Panda, S.; Schiavon, L.; Sivolella, S.; Biasetto, L.; Del Fabbro, M. The Impact of Bioceramic Scaffolds on Bone Regeneration in Preclinical In Vivo Studies: A Systematic Review. Materials 2020, 13, 1500. https://0-doi-org.brum.beds.ac.uk/10.3390/ma13071500
Brunello G, Panda S, Schiavon L, Sivolella S, Biasetto L, Del Fabbro M. The Impact of Bioceramic Scaffolds on Bone Regeneration in Preclinical In Vivo Studies: A Systematic Review. Materials. 2020; 13(7):1500. https://0-doi-org.brum.beds.ac.uk/10.3390/ma13071500
Chicago/Turabian StyleBrunello, Giulia, Sourav Panda, Lucia Schiavon, Stefano Sivolella, Lisa Biasetto, and Massimo Del Fabbro. 2020. "The Impact of Bioceramic Scaffolds on Bone Regeneration in Preclinical In Vivo Studies: A Systematic Review" Materials 13, no. 7: 1500. https://0-doi-org.brum.beds.ac.uk/10.3390/ma13071500